Abstract: Structured exercise in obese diabetic patients with chronic kidney disease: a randomized controlled trial. Patients with type 2 diabetes, obesity, and chronic kidney disease (CKD) are generally physically inactive, have a high mortality rate, and may benefit from an exercise program. However, there have been no randomized controlled trials to determine the benefits of exercise training in this population. This study seeks to substantiate the hypothesis that increasing energy expenditure by exercise training in the obese diabetic patient with CKD will result in the following benefits: 1. Renal benefits, including reduction in proteinuria and stabilization of glomerular filtration rate (GFR) 2. Cardiovascular benefits, including decreased blood pressure, decreased heart rate, and increased exercise tolerance. 3. Improved glucose control (lower glycated hemoglobin), lipid control (decreased cholesterol with improved atherogenic profile) 4. Improved body composition (weight loss, increased lean body mass and decreased fat mass). 5. Decreased inflammation (assessed by high-sensitivity C-reactive protein), endothelial dysfunction (assessed by flow-mediated dilatation), and oxidative stress (assessed by reduced glutathione). 6. Increased health-related quality of life. In preparation for this proposal, we performed a 24-week randomized controlled feasibility study comparing aerobic exercise plus optimal medical management to medical management alone in patients with type 2 diabetes, obesity (BMI > 30 kg/m2), and stage 2-4 CKD (eGFR 15-90 mL/min/1.73m2) with persistent proteinuria of > 200 mg/g. Subjects randomized to exercise underwent thrice weekly aerobic training for 6 followed by 18 weeks of supervised home exercise. Exercise training resulted in a significant improvement in exercise duration, resting systolic blood pressure, and proteinuria. We now propose a larger-scale randomized controlled trial to determine the effects of exercise on renal functions, cardiovascular fitness, inflammation, and oxidative stress in diabetic patients with CKD. This will be a 52-week randomized controlled study. Subjects randomized to exercise will undergo 12 weeks of structured exercise training followed by 40 weeks of supervised home exercise (total duration of study 1 year). The primary outcome variable will be a decrease in proteinuria (albuminuria and total proteinuria) at 12 and 52 weeks. Blood pressure (BP), glycated hemoglobin, lipid profile, C-reactive protein (CRP) levels, and body weight and composition will be secondary outcome variables. In addition we will examine indices of endothelial dysfunction (by flow-mediated dilatation) and oxidative stress (plasma and urine malondialdehyde). Moreover, since blood pressure is such an important determinant of renal outcomes, we will take advantage of the VA Telehealth program to monitor home BPs in all subjects. We will also perform Quality of Life (QoL) evaluations, as such data are important for this project in order to establish that exercise can produce a meaningful improvement in perception of health in this population, as well as the Index of Coexistent Diseases (ICED) to measure comorbidities to determine if comorbid conditions had any influence on the outcomes of the study. The Center for Epidemiologic Studies Depression Scale (CES-D) will also be used to determine the influence of depression (covariate) on study outcomes and adherence with the study objectives. This study will directly address the effects of a structured exercise program in a patient population at high risk for cardiovascular complications. We will specifically address the novel idea that exercise will not only improve cardiovascular fitness but will also ameliorate the renal complications resulting from diabetes. PUBLIC HEALTH RELEVANCE: Significance and relevance to VA patient care Diabetic kidney disease is the most common etiology of end-stage renal disease (ESRD) in the VA as well as the U.S. and is a major cause of morbidity and mortality in diabetic veterans. Renal dialysis offers only short-term survival in these patients, with a one-year mortality rate of about 25%. Moreover, the cost of renal replacement therapy contributes substantially to overall health care expenditure. The estimated annual cost of the U.S. ESRD program is in excess of $23 billion, of which nearly half is used for the care of diabetic patients. ESRD costs were nearly 7% of total Medicare spending in 2008. If exercise is ultimately shown to have a beneficial effect on kidney function including delaying or prevention of progression to ESRD, this modality could conceivably lead to substantial human benefits and cost savings in the VA and general U.S. population.